Genhong Cheng, Ph.D.
Genhong Cheng is a Professor in the Department of Microbiology, Immunology & Molecular Genetics at the University of California Los Angeles (UCLA). Dr. Cheng graduated from Wuhan University with a bachelor’s degree in 1984. He received his Ph.D. in molecular biology from the Albert Einstein School of Medicine in 1990. He was trained as a postdoctoral researcher by Dr. David Baltimore at Rockefeller University and the Massachusetts Institute of Technology. Dr. Cheng has been a faculty member at UCLA since 1996, engaged in multidisciplinary research in infection, immunity, cancer and metabolism. Dr. Cheng pioneered in discovering TLR-mediated IFN induction pathways responsible for cloning of TRAF3 and TANK in IFN and NF-κB pathways. Dr. Cheng also pioneered in identifying a novel IFN-mediated anti-inflammatory gene program, which prevents inflammatory diseases such as MS and IBD but also contributes to secondary or chronic bacterial and viral infections. Dr. Cheng’s work on numerous antiviral IFN stimulatory genes (ISG) including CH25H has developed a novel strategy to use ISG products such as 25HC as broad antiviral agents against emerging pathogenic viruses such as SARS-CoV-2，Ebola and Zika. Dr. Cheng has published more than 230 papers in high impact journals and has won several scientific achievement awards including the Stallman Award from the American Society for Leukemia and Lymphoma. He was elected as a Fellow of the American Association for the Advancement of Science (AAAS) in 2012 and as a member of the American Academy of Microbiology in 2018.
Host Immune and Inflammatory Responses to Infections, Tissue Injuries, Cancers and Metabolic Challenges: Our research at UCLA is aimed towards understanding innate and adaptive immune responses in host defense against infections and cancers, as well as their associations with inflammatory and metabolic diseases. Upon recognizing pathogenic infections and other environmental challenges, host cellular receptors can trigger a series of signal transduction and gene expression networks (gene programs) to initiate innate immune responses. These responses can, for example, control the replication and spread of bacteria and viruses by activating phagocytes and inducing the release of antimicrobial proteins and/or type I interferons. In addition, innate immune responses are essential in the development of humoral and cellular adaptive immunity by enhancing antigen presentation and upregulating co-stimulatory molecules. A defect at any step of this well-coordinated process can increase host susceptibility to infection. On the other hand, overactive immune responses can also lead to multiple inflammatory disorders and metabolic syndromes. We hope to understand both the similarities and differences in host immune responses to infections by different types of pathogens. We also hope to better appreciate how we balance immune and inflammatory responses, and how these responses influence other homeostatic and metabolic processes. Our goal is to develop novel strategies to enhance our immunity against infections and tumor challenges, while preventing or inhibiting inflammatory and metabolic diseases.
Major Contributions to Science
- We were the first to identify TNF receptor associated factor 3 (TRAF3), one of a family of proteins now recognized as major mediators of multiple signal transduction pathways activated not only by TNF receptors but also by toll-like receptors and others involved in both innate and adaptive immune responses. While other TRAF proteins function as positive regulators for the canonical NF-κB pathway, we found that TRAF3 is a critical negative regulator for the non-canonical (n.c.) NF-κB pathway by controlling the basal levels of NF-κB inducing kinase (NIK) and subsequently preventing the processing of the inactive p100 to the active p52 NF-κB subunit. TRAF3-deficient B-cells have a constitutively activated n.c. NF-κB pathway and enhanced survival, which resembles phenotypes associated with autoimmune diseases. Interestingly, TRAF3-deficient mice are hypoglycemic and die within two weeks after birth, which can be rescued by a compound knockout of critical molecules in the n.c. NF-κB pathway. We also identified a signaling complex with both positive and negative regulators of n.c. NF-κB activation through the ubiquitination and degradation of NIK. Interestingly, deletion mutations of TRAF3 and genetic silencing of cIAP1 and cIAP2 are found in patients with multiple myeloma, which is associated with high levels of NF-κB activity. We also identified a novel negative feedback mechanism involving IKKα that prevents constitutive activation of the n.c. NF-κB pathway.
- Cheng, G., Cleary, A.M., Ye, Z.S., Hong, D.I., Lederman, S., and Baltimore, D. Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science 267:1494-1498, 1995. PMID: 7533327
- He, J.Q., Zarnegar, B., Yamazaki, S., Oganesyan, G., Saha, , Doyle, S., Dempsey, P., and Cheng, G. Rescue of TRAF3 null mice by p100 NF-κB deficiency. J Exp Med. 203:2413-2418, 2006. PMCID:PMC2118128
- Zarnegar, B.J., Wang, Y., Mahoney,J., Dempsey,P.D., Cheung H.H., He,J., ShibaT., YangX., Yeh,W.C., Mak,T.W., Korneluk,R.G., Cheng, G. Activation of noncanonical NF-κB requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2, TRAF3 and the kinase NIK Nature Immunology 9:1371-8, 2008. PMCID:PMC2676931
- Razani, B., Zarnegar, B., Ytterberg, A.J., Shiba, T., Dempsey, P., Ware, C.F., Loo, J.A., Cheng, G.. Negative Feedback in Non-canonical NF-kB Signaling Modulates NIK Stability Through IKKα-mediated Phosphorylation Science Signaling, 3:ra41., 2010, PMCID:PMC2913610
- We identified several major signaling molecules involved in the activation of innate immune responses. We found TRAF3 as a critical signaling mediator integrating distinct viral recognition pathways including TLRs and RIG-I into a common interferon production pathway. We found RIP2 as an essential molecule in the Nod-mediated signaling pathway for host defense against bacterial infection. We found DDX41 as an important pattern recognition receptor that can specifically recognize cyclic di-GMP and cyclic di-AMP.
- Oganesyan, G., Saha, SK, Guo, B., He, J., Shahangian, A., Zarnegar B., Perry, AK., Cheng, G. Critical role of TRAF3 in the Toll-like receptor-dependent and independent antiviral response. Nature, 439:208-211, 2006. PMID:16306936
- Chin, A. I., Dempsey, P. W., Bruhn, K., Miller, J. F., Xu, Y., and Cheng, G. Involvement of Receptor Interacting Protein 2 in Innate and Adaptive Immune Responses. Nature, 416:190-194, 2002. PMID:11894097
- Ouyang, S., Song, X., Wang, Y., Ru, H., Shaw, N., Jiang, Y., Niu, F., Zhu, Y., Qiu, W., Parvatiyar, K., Li, Y., Zhang, R., Cheng, G., Liu, Z.J. Structural Analysis of the STING Adaptor Protein Reveals a Hydrophobic Dimer Interface and Mode of Cyclic di-GMP Binding. Immunity, 36:1073-86, PMCID:PMC3654694
- Parvatiyar, K., Zhang, Z., Teles, R.M., Ouyang, S., Jiang, Y., Iyer, S.S., Zaver, S.A., Schenk, M., Zeng, S., Zhong, W., Liu, Z.J., Modlin, R.L., Liu, Y., Cheng, G. DDX41 recognizes bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol. 13:1155-61, 2012. PMCID:PMC3501571. (Cover story with News and Views)
- We were among the first in connecting toll-like receptors (TLRs) to IFN-I infection and showing that IFN-I is induced in response to not only viral but also bacterial infections. We have subsequently demonstrated that mice lacking the IFN-I receptor (IFNAR1), while more sensitive to viral infections, are more resistant to many bacterial infections, suggesting that IFN may suppress host defenses against bacteria. We have recently made significant contributions in systemically identifying antiviral interferon stimulated genes (ISGs) and determining their mechanisms of action against vital infections. In contrast to the numerous advances made in understanding Type I IFN induction, the molecular mechanisms by which Type I IFN suppresses viral infection and replication are less well understood. Our recent studies using microarray and RNAseq analysis have identified over 300 ISGs. We have taken a systematic approach to measure the antiviral activities of individual ISGs against VSV and MHV68 viral infections.
- Doyle, S.E., Vaidya, S.A., O’Connell, R., Dadgostar, H., Dempsey, P.W., Wu, T.T., Rao, G., Sun, R., Haberland, M.E., Modlin, R.L., Cheng, G. IRF3 Mediates a TLR3/TLR4-Specific Antiviral Gene Program. Immunity 17:251-263, 2002. PMID:12354379
- Liu, S.Y., Sanchez, D.J., Aliyari, R., Cheng, G. Systematic Identification of Type-I and Type-II Interferon Induced Anti-Viral Factors. PNAS 109:4239-44, 2012. PMCID: PMC3306696.
- Chow, E.K., Castrillo, A. Shahangian, A., Pei, L., O’Connell, R.M., Modlin, R.L., Tontonoz, P., Cheng, G. A role for IRF3-dependent RXRalpha repression in hepatotoxicity associated with viral infections. J Exp Med. 203:2589-2602, 2006, PMCID: PMC2118146
- Ma, F., Liu, S.Y., Razani, B., Arora, N., Li, B., KagechikaHYPERLINK “https://www.ncbi.nlm.nih.gov/pubmed/?term=Kagechika%20H%5BAuthor%5D&cauthor=true&cauthor_uid=25417649”, H., Tontonoz, P., NúñezHYPERLINK “https://www.ncbi.nlm.nih.gov/pubmed/?term=N%C3%BA%C3%B1ez%20V%5BAuthor%5D&cauthor=true&cauthor_uid=25417649”, V., Ricote, M., Cheng, G. Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon. Nat HYPERLINK “https://www.ncbi.nlm.nih.gov/pubmed/25417649″CommunHYPERLINK “https://www.ncbi.nlm.nih.gov/pubmed/25417649”. 5:5494, 2014. PMCID: PMC4380327
- We have further demonstrated that, in addition to its well-known antiviral function, IFN-I also plays a very important role in anti-inflammatory responses through induction of IL-27 and IL-10, which protects host from cytokine storms during acute infections and also protects host from autoimmune diseases such as Experimental Allergic Encephalomyelitis (EAE) and inflammatory bowel disease. On the other hand, we found that strong or sustained activation of this IFN-I-mediated anti-inflammatory pathway may also lead to acute infectious diseases such as post influenza secondary bacterial pneumonia and chronic infectious diseases such as Mycobacterial Leprae. Most recently, we have demonstrated that influenza infection in the lung can strongly alter microbiota profile in the gut through the IFN-I-mediated anti-inflammatory gene program.
- Shahangian, A., Chow, E.K., Tian, X., Kang, J.R., Ghaffari, A., Liu, S.Y., Belperio, J.A., Cheng, G., Deng, J.C. Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice. J Clin Invest. 119:1910-20, 2009. PMCID: PMC2701856.
- Teles, R.M., Graeber, T.G., Krutzik, S.R., Montoya, D., Schenk, M., Lee, D.J., Komisopoulou, E., Kelly-Scumpia, K., Chun, R., Iyer, S.S., Sarno, E.N., Rea, T.H., Hewison, M., Adams, J.S., Popper, S.J., Relman, D.A., Stenger, S., Bloom, B.R., Cheng, G., Modlin, R.L. Type I Interferon Suppresses Type II Interferon-Triggered Human Anti-Mycobacterial Responses. Science 339:1448-53, 2013. PMCID: PMC3653587
- Wilson, E.B., Yamada, D.H., Elsaesser, H., Herskovitz, J., Deng, J., Cheng, G., Aronow, B., Karp, C.L., Brooks, D.G. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340:202-7, 2013. PMCID: PMC3704950.
- Deriu, E., Boxx, G.M., He, X., Pan, C., Benavidez, S.D., Cen, L., Rozengurt, N., Shi, W., Cheng, G.. Influenza Virus Affects Intestinal Microbiota and Secondary Salmonella Infection in the Gut through Type I Interferons. PLoS Pathogen 5;12(5):e1005572. 2016. doi: 10.1371/journal.ppat.1005572. eCollection. PMCID:PMC4858270.
- We have made significant contributions in the development of broad spectrum antiviral therapies against different strains of influenza and different types of viruses, including emerging pathogenic viruses such as Ebola and Zika (ZIKV) viruses. Traditional strategies to develop inhibitors to specific viral targets require a thorough understanding of their enzymes and large screens for possible targets, which is a lengthy process that can delay drug development and also faces the problem of eventual drug resistance. As emerging viral pathogens such as avian flu, SARS, Ebola and ZIKV continue to impact the health and economy of our modern society, we must consider novel strategies to develop broad spectrum antiviral agents. Based on our knowledge of host immune responses to viral infections, we have recently developed multiple broad antiviral agents, including 25-Hydroxycholesterol, which effectively inhibited all the enveloped viruses we tested and protected animal models against virus-associated diseases such as ZIKV-induced microcephaly. We have also developed a novel method for screening large libraries of mutant viruses for possible development as live attenuated vaccines. We used this method to generate a live attenuated influenza strain that can provide cross-protection against multiple strains of influenza, including H1N1, H3N1, H3N2 and H5N1. In this proposal, we will further characterize the immune responses to influenza infection and vaccination.
- Liu, S.Y., Aliyari, R., Chikere, K., Li, G., Marsden, M.D., Smith, J.K., Pernet, O., Guo, H., Nusbaum, R., Zack, J.A., Freiberg, A.N., Su, L., Lee, B., Cheng, G.. Cholesterol-25-Hydroxylase Broadly Inhibits Viral Replication by Production of 25-Hydroxycholesterol. Immunity 38:92-105, 2012. PMCID:PMC3698975
- Li C, Deng YQ, Wang S, Ma F, Aliyari R, Huang XY, Zhang NN, Watanabe M, Dong HL, Liu P, Li XF, Ye Q, Tian M, Hong S, Fan J, Zhao H, Li L, Vishlaghi N, Buth JE, Au C, Liu Y, Lu N, Du P, Qin FX, Zhang B, Gong D, Dai X, Sun R, Novitch BG, Xu Z, Qin CF, Cheng G. 25-Hydroxycholesterol Protects Host against HYPERLINK “https://www.ncbi.nlm.nih.gov/pubmed/28314593″ZikaHYPERLINK “https://www.ncbi.nlm.nih.gov/pubmed/28314593” Virus Infection and Its Associated Microcephaly in a Mouse Model. Immunity. 2017 Mar 21;46(3):446-456. doi: 10.1016/j.immuni.2017.02.012. Epub 2017 Mar 14. PMID: 28314593
- Wang L, Liu SY, Chen HW, Xu J, Chapon M, Zhang T, Zhou F, Wang YE, Quanquin N, Wang G, Tian X, He Z, Liu L, Yu W, Sanchez DJ, Liang Y, Jiang T, Modlin R, Bloom BR, Li Q, Deng JC, Zhou P, Qin FX, Cheng G. Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets. Cell Host Microbe. 2017 Mar 8;21(3):334-343. doi: 10.1016/j.chom.2017.02.007. PMID: 28279345
- Wang, L., Valderramos, S.G., Wu, A., Ouyang, S., Li, C., Brasil, P., Bonaldo, M., Coates, T., Nielsen-Saines, K., Jiang, T., Aliyari, R., Cheng, G. From Mosquitos to Humans: Genetic Evolution of Zika Virus Cell Host & Microbe 19(5):561-5, 2016. PMID:27091703
List of Published Work in My Bibliography including over 200 peer reviewed papers: